The overall goal of this application is to investigate the interactions between specific genetic variants and the social environment, in the etiology of posttraumatic stress disorder (PTSD). We propose this work in direct response to PAR 08-065 "NIH Revision Awards for Studying Interactions Among Social, Behavioral, and Genetic Factors in Health (R01)". The proposed work will take advantage of a unique opportunity to add a genetic component to an ongoing multi-level longitudinal study of posttraumatic stress disorder (PTSD) in members of the Detroit Neighborhood Health Study (DNHS), a representative population-based sample of 1500 urban residents of Detroit (DA22720;PI: Sandro Galea). No existing work, as far as we are aware, has assessed how features of the social environment modify genetic influences on PTSD. The DNHS offers a comprehensive assessment of both individual and community-level environmental exposures and is, therefore, a unique resource for a multi-level study of gene- environment interaction. Moreover, the DNHS is already funded to collect blood samples from participants. Funding for the current proposal would enable us to extract DNA and genotype bloods collected in this study as well as provide salary coverage for molecular and statistical genetics expertise. The aims of this proposed supplemental study are (1) To assess whether genetic variants implicated in the neurobiology of PTSD (e.g., SLC6A4, FKBP5), modify the longitudinal relation between potentially traumatic events and risk of PTSD in residents of Detroit, and (2) To assess whether genetic variants implicated in the neurobiology of PTSD (e.g., SLC6A4, FKBP5), modify the longitudinal relation between features of the social environment (e.g., economic disadvantage) and the risk of PTSD in residents of Detroit. PUBLIC HEALTH RELEVANCE: This is a revision award submitted in response to PAR 08-065 "NIH Revision Awards for Studying Interactions Among Social, Behavioral, and Genetic Factors in Health (R01)". The overall goal of our revision application is to investigate the interactions between specific genetic variants and features of the social environment in the etiology of substance abuse and posttraumatic stress disorder (PTSD). The proposed Revision Award adds genotyping to already funded work (DA022720) to conduct the first multi- level study of gene-environment interaction in PTSD to date at minimal cost. The identification of genetic variants that moderate susceptibility to PTSD will provide clues to the pathophysiology of the disorder. That, in turn should facilitate the search for newer more effective pharmacological agents for PTSD treatment and prevention. Understanding factors that may shape vulnerability to PTSD is critically important for the development of effective interventions that can mitigate the consequences of PTSD. In addition, this study involves a unique collaboration between epidemiologists who bring to this work a social ecologic perspective, epidemiologists with expertise in psychoneuroimmunology and collaborators with expertise in psychiatric epidemiology, molecular and statistical genetics. Therefore, although this study is specifically focused on PTSD as its key categorical outcomes of interest, insights from this work may help guide our understanding of how ecologic stressors influence a range of heath outcomes, including drug abuse/dependence.